tbuckley/cabot-search huggingface dataset:
Abstract 3027: Elucidating the role of glutamine metabolism in head &amp; neck squamous cell carcinoma
Authors: Michael Allevato, Yumi Yokoyama, Robert Wild, J. Silvio Gutkind
Journal: Cancer Research (2022)

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 14,600 deaths each year in the United States alone. HNSCC is associated with human papillomavirus (HPV) infection, tobacco use, and abusive alcohol intake. Without truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. Unfortunately, these treatments are associated with significant morbidity and a reduction in quality of life. Immunotherapies have recently revolutionized HNSCC treatment, but &amp;lt;20% of patients exhibit clinical responses, albeit often not durable (Saddawi-Konefka et al. Frontiers in Oncology 2021). This highlights the unmet need to identify novel therapeutic options and biomarkers predicting a more favorable response to maximize the efficacy of targeted cancer strategies for HNSCC treatment. Glutamine is a conditionally essential amino acid for rapidly proliferating cancer cells making glutamine pathway inhibition an attractive approach for anti-cancer therapy. We found that treatment with the broad glutamine antagonist sirpiglenastat (DRP-104), which irreversibly inhibits all known enzymes involved in glutamine metabolism, results in metabolically halted cell growth in a large panel (n=8) of HPV- and HPV+ HNSCC cell lines (IC50 of 0.2-25uM). Interestingly, HNSCC cells bearing genetic alterations in PIK3CA and PTEN were significantly more sensitive to glutamine antagonism than unaltered HNSCC cells. The dependence of glutamine in HNSCC growth and the increased sensitivity of PIK3CA/PTEN aberrant cells was also observed in orosphere assays and HNSCC tumor xenografts in mice in vivo. We next explored the mechanism of glutamine suppression in HNSCC by integrating the results from genome-wide CRISPR-Cas9 knockout library screens and broad-spectrum metabolomics analysis. Both approaches converged on the identification of a dysregulated metabolic pathway that represents a synthetic lethal vulnerability that can be exploited via targeted therapies. Our data suggest that broad glutamine antagonism using sirpiglenastat (DRP-104) has therapeutic potential in HNSCC by dismantling cancer metabolism and sensitizing cells to additional perturbations leading to specific cell death. A clinical trial of sirpiglenastat (DRP-104) is currently ongoing (NCT04471415). Citation Format: Michael Allevato, Yumi Yokoyama, Robert Wild, J. Silvio Gutkind. Elucidating the role of glutamine metabolism in head &amp; neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3027.
Abstract 6244: A T cell engaging bispecific antibody utilizing a bivalent tumor-selective folate receptor alpha binding arm for the treatment of ovarian cancer
Authors: Brian C. Avanzino, Kirthana Prabhakar, Pranjali Dalvi, Sharon Hartstein, Hannes Kehm, Aarti Balasubramani, Andrew A. Boudreau, Ben Buelow, Karen Chang, Laura M. Davison, Suhasini Iyer, Vidyut Kalwit, Harbani Malik-Chaudhry, Will Pierson, Geovanni Pineda, Udaya S. Rangaswamy, Sowmya Saiganesh, Ute Schellenberger, Harshad S. Ugamraj, Roland Buelow, Jocelyn Chapman, Nathan D. Trinklein, Katherine E. Harris
Journal: Cancer Research (2022)

Abstract The use of T cell engagers (TCEs) to treat solid tumors in humans is challenging, and several have been limited by narrow therapeutic windows due to substantial toxicity. Dose-limiting toxicities of TCEs include cytokine release syndrome (CRS) and on-target, off-tumor toxicities since many solid tumor target antigens are also expressed in healthy tissues, albeit at lower levels. While there have been improvements in the clinical management of immune-mediated toxicities such as CRS, on-target, off-tumor effects remain one of the primary challenges of using TCEs for treatment of solid tumors. Here, we describe TNB-928B, a novel fully human TCE that is bivalent for folate receptor alpha (FRα) that selectively targets FRα overexpressing tumor cells yet avoids targeting cells that express low levels of FRα found in normal human cells. Selectivity is conferred by an avidity effect of the FRα targeting arm in combination with a unique low-affinity CD3 arm and is anticipated to reduce the risk of adverse events in normal cells expressing low levels of FRα. TNB-928B induces preferential effector T cell activation, proliferation, and cytotoxic activity with minimal cytokine release, compared to a positive control containing OKT3, thereby improving the therapeutic index. Moreover, TNB-928B exhibits substantial ex vivo tumor cell lysis using endogenous T cells and is effective in vivo promoting T cell infiltration and tumor regression in mouse models of ovarian cancer. Together, these results demonstrate TNB-928B represents a novel next generation immunotherapy modality with enhanced safety and specificity for the treatment of ovarian cancer. Citation Format: Brian C. Avanzino, Kirthana Prabhakar, Pranjali Dalvi, Sharon Hartstein, Hannes Kehm, Aarti Balasubramani, Andrew A. Boudreau, Ben Buelow, Karen Chang, Laura M. Davison, Suhasini Iyer, Vidyut Kalwit, Harbani Malik-Chaudhry, Will Pierson, Geovanni Pineda, Udaya S. Rangaswamy, Sowmya Saiganesh, Ute Schellenberger, Harshad S. Ugamraj, Roland Buelow, Jocelyn Chapman, Nathan D. Trinklein, Katherine E. Harris. A T cell engaging bispecific antibody utilizing a bivalent tumor-selective folate receptor alpha binding arm for the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6244.
Errors in Figure
Journal: JAMA Network Open (2022)

In the Original Investigation titled "Adverse Childhood Experiences and Subsequent Chronic Diseases Among Middle-aged or Older Adults in China and Associations With Demographic and Socioeconomic Characteristics," 1 published October 25, 2021, there were errors in the numbers of participants excluded and those without data in the CHARLS 2014 survey that appeared in the second-row box of Figure 1's flow diagram.These should have been given as 3358 participants excluded and 1549 without data in the CHARLS 2014 survey.This article has been corrected.
Abstract 3204: Differential expression of angiogenesis-associated genes in smoker and non-smoker lung adenocarcinoma patients
Authors: Shubhangi Singh, Santanu Dasgupta, Elba A. Turbat-Herrera, Seema Singh, Ajay P. Singh
Journal: Cancer Research (2022)

Abstract Tobacco smoke (TS) is one of the most prominent risk factors for lung and several other malignancies. Toxic chemicals present in TS induce DNA damage leading to carcinogenic mutations. Moreover, TS can also cause epigenetic and gene expression changes in tumor and other cells of the tumor microenvironment, especially through its addictive component nicotine. We and others have reported that nicotine promotes tumor angiogenesis via its direct impact on the endothelial cells or by altering the cancer cell secretome. In this study, we wanted to explore the association of smoking habits with the differential expression of angiogenesis-related genes in lung adenocarcinoma (LUAD) patients. Gene Set Enrichment Analysis (GSEA) identified a set of 48 angiogenesis-related genes that were surveyed for differential expression in smoker versus non-smoker patients in The Cancer Genomic Atlas (TCGA) database using an interactive web application, UALCAN. Gender and age of the LUAD patients were considered as confounding variables since patients of different age groups and gender can have biological and physiological differences, which could influence gene expression regardless of the smoking habits. We identified a total of fourteen differentially-expressed genes, of which four (HTATIP2, NCL, SPHK1, and VEGFA) were overexpressed and ten (AGGF1, AMOT, C1GALT1, ERAP1, NPR1, PML, RNH1, SHH, SPINL5, and TNFSF12) were downregulated in LUAD of smokers than those of non-smokers. Five of the differentially-expressed genes (HTATIP2, NCL NPR1, PML, and TNFSF12) exhibited significantly different transcript levels in males versus females and three (SPHK1, AGGF1, and SPINK5) showed varying pattern of expression in LUAD of different age group patients. Literature survey found prior published evidence for an association of two of the fourteen differentially expressed genes (NCL and NPR) with nicotine exposure. Together, our findings identify smoking-associated angiogenic gene signatures that could be potential effectors of nicotine signaling that promotes cancer angiogenesis and should be validated further by conducting laboratory investigations. Citation Format: Shubhangi Singh, Santanu Dasgupta, Elba A. Turbat-Herrera, Seema Singh, Ajay P. Singh. Differential expression of angiogenesis-associated genes in smoker and non-smoker lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3204.
Abstract 1837: Low dose actinomycin D preferentially activates p53-p21 pathway in aerodigestive tract cancers: Implication for cyclotherapy
Authors: Adeoluwa A. Adeluola, A. R. M Ruhul Amin
Journal: Cancer Research (2022)

Abstract Actinomycin D (ActD) was the first anti-cancer antibiotic approved for the management of human cancers. However, the notorious toxicity profile limits its widespread application in cancers including cancers of the aerodigestive tract. Recent studies show that combining low-dose ActD with existing chemotherapies could potentially reduce the toxicity of chemotherapy drugs through p53 mediated cyclotherapy (protection of normal cells while eliminating cancer cells), a recently coined concept. An understanding of ActD’s effect on p53 signaling is critical for meaningful application of ActD in cyclotherapy-based combinations. This study evaluated the antitumor efficacy and mechanism of action of ActD in aerodigestive tract cancers. We found that ActD strongly inhibited the growth of a panel of aerodigestive tract cancer cell lines and induced efficient apoptosis although the sensitivity varies among cell lines. The IC50 values of ActD spanned between 0.021-2.96nM. Mechanistic studies revealed that ActD time- and dose-dependently increased the expression of total and phosphorylated p53 (ser15). Furthermore, ActD-induced apoptosis is dependent on p53 in cells expressing wild-type p53. Further studies demonstrated that ActD induced context-dependent differential expression of downstream targets p21 and PUMA without significant effects on p27. Interestingly, our study revealed that p53-p21 is the predominant pathway activated by low-dose ActD in cells with wild type p53. Therefore, our findings further rationalize the premise for future studies to explore the application of low-dose ActD as a chemoprotectant for cyclotherapy combinations in aerodigestive tract cancers. (Supported by NIH Grant P20GM103434 to the West Virginia IDeA Network for Biomedical Research Excellence) Citation Format: Adeoluwa A. Adeluola, A. R. M Ruhul Amin. Low dose actinomycin D preferentially activates p53-p21 pathway in aerodigestive tract cancers: Implication for cyclotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1837.
Abstract 6214: Detecting and characterizing extrachromosomal DNA in medulloblastoma at single-cell resolution
Authors: Owen Chapman, Sunita Sridhar, Jon D. Larson, Robert J. Wechsler-Reya, Jill Mesirov, Lukas Chavez
Journal: Cancer Research (2022)

Abstract Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive cancers, including medulloblastoma (MB), the most common malignant pediatric brain tumor. To assess the clinical import of ecDNA in MB, we applied computational methods to detect ecDNA to the genomes of a cohort of 468 MB patients and 31 MB model systems. Among patients, ecDNA was detected in 18% of tumors and carried threefold greater risk of mortality. Between sequential patient biopsies at initial diagnosis and subsequent relapse, we observed frequent structural variation at ecDNA loci and generation of new ecDNA sequences. Among model systems, ecDNA was found in 19 of 31 genomes (61%). Although ecDNA was far more prevalent among MB models than patients, the ecDNA genomic sequence was conserved between most patient-derived xenograft (PDX) models and their origin human tumors. EcDNA promotes high oncogene copy number, accelerated evolution of drug resistance and poor prognosis. Mechanistically, these behaviors are hypothesized to be consequences of intratumoral heterogeneity of ecDNA copy number; however, there are currently no methods to quantify the abundance and distribution of ecDNA across single cells in a tumor. We have previously identified a primary TP53-mutant SHH medulloblastoma tumor, which harbors multiple distinct lineages of ecDNA originating from different chromosomes. We have now simultaneously analyzed the accessible chromatin and gene expression in single cells of the human tumor and of a orthotopic mouse xenograft (PDX) derived for this tumor, using multiome single-cell ATAC-seq and gene expression (10X Genomics). By measuring scATAC-seq read depth at the ecDNA loci relative to the rest of the genome, we estimate ecDNA copy number in single cells. We observe substantial variation in the ecDNA copy number of cells in both the human tumor and the PDX, and strong association with transcription of ecDNA-amplified genes. We anticipate that this approach will illuminate mechanisms of ecDNA-mediated drug resistance, by revealing the sensitivity and population dynamics of ecDNA-containing cells under treatment pressure. Citation Format: Owen Chapman, Sunita Sridhar, Jon D. Larson, Robert J. Wechsler-Reya, Jill Mesirov, Lukas Chavez. Detecting and characterizing extrachromosomal DNA in medulloblastoma at single-cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6214.
Abstract 3643: The role of HBP1 in controlling breast cancer dormancy reawakening
Authors: Irwin H. Gelman, Seamus Degan, Henry G. Withers, Subrahmanya Anirudh Kaligotla Venkata
Journal: Cancer Research (2022)

Abstract At least 22% of breast cancer (BrCa) cases recur after 3 to 15 years, typically at metastatic sites such as the bone. Bone metastases derive from early disseminated tumor cells that become dormant because of interaction with specific cells that define the endosteal niche (EN) microenvironment. However, outside knowing that dormancy is driven by a p38MAPKhi, ERK1/2lo activation profile, our understanding of what factors regulate dormancy maintenance and reawakening is poor. We used a genomic shRNA screen to identify HBP1 as a suppressor of BrCa dormancy reawakening in a 3D-EN culture system. Our data indicate that under 3D-EN conditions, HBP1 is upregulated by p38MAPK, interacts with the metastasis suppressors, BRMS1 and BRMS1L, and with the histone modifiers, SIN3A and HDAC1-3. We hypothesize that HBP1 suppresses p38MAPK-mediated dormancy reawakening by complexing with BRMS1/BRMS1L/SIN3A to alter cell cycle gene expression through histone landscape remodeling. HBP1 suppresses the expression of cell cycle progression genes, such as MYC and CCND1, and concomitantly upregulates cyclin kinase inhibitors, p16 and p21. HBP1 RNA and protein levels are decreased in BrCa metastases relative to primary tumors, and this downregulation correlates with poorer overall survival. We are investigating whether the anti-histiminic drug, cyproheptadine, which upregulates HBP1 expression through the activation of p38MAPK, can suppress dormancy reawakening of BrCa cells in 3D-EN cultures and in in vivo models of bone dormancy using mouse mammary carcinoma D2A1 cell lines with varying abilities to form active or dormant metastatic bone colonization. Data will be shown addressing how cell-cell interactions and secretory factors between BrCa and bone EN cells facilitates dormancy signaling through a p38MAPK/HBP1/BRMS1 axis, and how drugs such as cyproheptadine agonize that pathway in order to prevent the reawakening that drives the growth of BrCa metastases in the bone, thereby increasing overall survival. Citation Format: Irwin H. Gelman, Seamus Degan, Henry G. Withers, Subrahmanya Anirudh Kaligotla Venkata. The role of HBP1 in controlling breast cancer dormancy reawakening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3643.
Abstract 5332: Prostate cancer targeting therapy using PSA promoter-driven perforin expression vector encapsulated in liposomes conjugated with anti-PSMA antibody
Authors: Kosuke Mizutani, Kyojiro Kawakami, Yasunori Fujita, Taku Kato, Manabu Takai, Daiki Kato, Koji Iinuma, Takuya Koie, Masafumi Ito
Journal: Cancer Research (2022)

Abstract Perforin secreted from cytotoxic T cells and natural killer cells play important roles in anti-tumor immunoreaction leading to cancer cell apoptosis. The aim of this study is to investigate whether perforin-rich tumor microenvironment could inhibit tumor growth. Advanced prostate cancer (PC) expresses high amount of prostate-specific antigen (PSA) that is a possible therapeutic target, therefore, we constructed a PSA promoter-driven perforin expression vector for its predominant expression in tumor microenvironment of PC. Prostate membrane-specific antigen (PSMA) expressed on PC cell surface is also an attractive therapeutic target. To deliver perforin expression vector to PC, it was encapsulated in liposomes conjugated with anti-PSMA antibody (PSMA-pLipo), then the anti-tumor effect of PSMA-pLipo was evaluated using docetaxel-resistant PC cell line, 22Rv1DR, expressing both PSA and PSMA. The conjugated anti-PSMA antibody on PSMA-pLipo recognized recombinant PSMA protein, and incubation with PSMA-pLipo induced perforin expression in 22Rv1DR cells but not in PC-3 cells not expressing both PSA and PSMA. Growth of 22Rv1DR and PC-3 cells was barely inhibited by PSMA-pLipo alone. Perforin functions in concert with cytotoxic lymphocytes, therefore anti-tumor effect of PSMA-pLipo was analyzed in the presence of human peripheral blood mononuclear cells (PBMCs). Low concentration of PSMA-pLipo with human PBMCs significantly inhibited growth of 22Rv1DR cells but not PC-3 cells. High concentration of PSMA-pLipo with human PBMCs showed nearly complete inhibition of 22Rv1DR cell growth. In a mouse xenograft model implanted with 22Rv1DR cells, PSMA-pLipo was intravenously administrated via tale vein and tumor volume was monitored. PSMA-pLipo inhibited growth of 22Rv1DR cells compared to injection of anti-PSMA antibody alone. The data presented here suggest that gene therapy expressing perforin specifically in PC cells could be a novel therapy for advanced PC. Citation Format: Kosuke Mizutani, Kyojiro Kawakami, Yasunori Fujita, Taku Kato, Manabu Takai, Daiki Kato, Koji Iinuma, Takuya Koie, Masafumi Ito. Prostate cancer targeting therapy using PSA promoter-driven perforin expression vector encapsulated in liposomes conjugated with anti-PSMA antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5332.
Abstract 2159: PRMT5 inhibitor PRT543 displays potent antitumor activity in U2AF1S34F and RBM10LOF spliceosome-mutant non-small cell lung cancer <i>in vitro</i> and <i>in vivo</i>
Authors: Jack Carter, Koichi Ito, Venkat Thodima, Monisha Sivakumar, Michael Hulse, Joseph Rager, Komali Vykuntam, Neha Bhagwat, Kris Vaddi, Bruce Ruggeri, Peggy Scherle
Journal: Cancer Research (2022)

Abstract PRMT5 (protein arginine methyltransferase 5) is a major Type II PRMT, which catalyzes the symmetric dimethylation of protein arginine residues (sDMA). As an epigenetic regulator, PRMT5 plays essential roles in promoting cancer growth and survival, including through mechanisms that control alternative splicing and RNA processing, and the expression of DNA damage repair genes. Spliceosome mutations have been suggested to represent a potential biomarker for PRMT5 inhibitors, and our previous work highlighted this sensitivity in SF3B1R625C/G expressing uveal melanoma cells. Here, we highlight in vitro and in vivo activity of PRT543, a potent, selective, and orally available PRMT5 inhibitor, in cancer cells harboring mutations in other spliceosome factors such as U2 small nuclear RNA auxiliary factor 1 (U2AF1) and RNA binding motif protein 10 (RBM10). Mutations in U2AF1 (including S34F hotspot mutations) and RBM10 (primarily loss of function (LOF) mutations) occur in 5-10% of all non-small cell lung cancers (NSCLC). Cell proliferation (10-day assay) was assessed in a panel of NSCLC cell lines treated with PRT543, either wild-type or harboring U2AF1S34F or RBM10LOF mutations. Strikingly, both U2AF1S34F and RBM10LOF cell lines were significantly more sensitive to PRT543 compared to wild-type cell lines. Furthermore, PRT543 induced significant dose-related tumor growth inhibition at well-tolerated doses in cell-line derived xenograft (CDX) models harboring the U2AF1S34F or RBM10LOF mutation. Consistent with our previous findings in other tumor types, PRT543 decreased expression of DNA damage repair-associated genes (e.g. BRCA1, RAD51AP1, FANCA, and FANCL) in U2AF1S34F or RBM10LOF mutant NSCLC cells. Combination with PRT543 increased the effectiveness of specific chemotherapeutic agents in both in vitro and in vivo (CDX) models of U2AF1S34F and RBM10LOF NSCLC. Efficacy studies in patient-derived xenograft (PDX) models, as well as genomic profiling of spliceosome-mutant cellular models in response to PRT543 are ongoing. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831). Citation Format: Jack Carter, Koichi Ito, Venkat Thodima, Monisha Sivakumar, Michael Hulse, Joseph Rager, Komali Vykuntam, Neha Bhagwat, Kris Vaddi, Bruce Ruggeri, Peggy Scherle. PRMT5 inhibitor PRT543 displays potent antitumor activity in U2AF1S34F and RBM10LOF spliceosome-mutant non-small cell lung cancer in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2159.